Mitochondrial reactive oxygen species mediates nicotine-induced hypoxia-inducible factor-1伪 expression in human non-small cell lung cancer cells

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• 作者：Lili Guo¹ ; Lin Li¹ ; Weiqiang Wang ; Zhenhua Pan ; Qinghua Zhou ; ^{zhouqh1016@yahoo.com.cn} ; Zhihao Wu ; ^{zwu2ster@gmail.com}
• 关键词：Nicotine ; Hypoxia-inducible factor 1伪 ; Mitochondria ; Reactive oxygen species ; Lung cancer metastasis
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2012
• 期刊代码：19_09254439
• 类别：bio
• 出版时间：June, 2012
• 卷：1822
• 期：6
• 页码：852-861
• 文件大小：1125 K

摘要

Cigarette smoking is not only a documented risk for lung carcinogenesis but also promotes lung cancer development. Nicotine, a major component of cigarette smoke but not a carcinogen by itself, has been found to induce proliferation, invasion and metastasis of non-small cell lung cancer (NSCLC). Here we reported that proinvasive effect of nicotine is analogous to that of hypoxia and involves stabilization and activation of hypoxia-inducible factor (HIF)-1伪, a key factor in determining the presence of HIF-1 and expression of its downstream metastasis-associated genes. Furthermore, nicotine-induced upregulation of HIF-1伪 was dependent on mitochondria-derived reactive oxygen species (ROS). Ecotopic expression of mitochondrial targeted catalase effectively prevented nicotine-induced accumulation of HIF-1伪 protein. In addition, we demonstrated that the effect of nicotine in upregulation of HIF-1伪 was mediated by Dihydro-尾-erythroidine (Dh尾E)-sensitive nicotine acetylcholine receptors (nAChRs) and required synergistic cooperation of Akt and mitogen-activated protein kinase (MAPK) pathways. These results suggest that exposure to nicotine could mimic effects of hypoxia to stimulate HIF-1伪 accumulation and activity that might underlie the high metastatic potential of lung cancer.